WHITE PAPER THE 2014 LUGANO CLASSIFICATION

1 THE 2014 LUGANO CLASSIFICATION1 WHITE PAPERA uthors:Bruce D. Cheson, MD; Rudresh Jarecha, DNB, DMRE; Kelie Luby, MS; Annette Schmid, PhD1 Cheson B, Fisher R, Barrington S, Cavalli F, Schwartz L, et al: Recommendations for Initial Evaluation, Staging, and Response Assessent of Hodgkin and non-Hodgkin Lymphoma: The LUGANO CLASSIFICATION . J Clin Oncol 32:3059-3067, the New Cheson Criteria in Lymphoma Clinical TrialsLYMPHOMA ASSESSMENT GUIDELINESThe LUGANO CLASSIFICATION , published in August 2014 , is the 2nd revision to the first universally accepted guidelines on assessing Lymphoma therapeutic response/progression in clinical trials.

2 The 2014 LUGANO CLASSIFICATION modernizes recommendations for the assessment of lymphoma by removing ambiguity in the application of the criteria in forthcoming lymphoma clinical trials. This will facilitate the comparison of patients and results by providing a standardized guidance on how data should be analyzed for response to therapy. Implementation of the LUGANO CLASSIFICATION for your specific therapeutic, patient population and indication should be prospectively defined in protocol. This includes interpretation of CT, imaging schedules for CT and PET scans, PET scoring implications, rules for handling missing lesions/anatomy, and rules around challenging scenarios for the given therapeutic under investigation.

3 Additionally, given that the scans have such an important role in response outcome, robust imaging guidelines are essential to a successful clinical trial in , there is no better way to communicate how criteria are applied in a protocol /trial than to use example cases that are made available to both the Principal Investigators and the central readers. PAREXEL in conjunction with Dr. Bruce Cheson is pleased to present here our recommendations on using the 2014 LUGANO CLASSIFICATION in Lymphoma Clinical JOURNEY. OUR | 2 YOUR JOURNEY. OUR | 2 NODAL SITE LDI > CM BY CTNON-NODAL SITE PRESENT/CONSISTENT WITH LYMPHOMA BY CTSPLENIC INVOLVEMENT> 13 CM IN VERTICAL LENGTH (CRANIAL TO CAUDAL) BY CTHEPATIC INVOLVEMENTDIFFUSELY INCREASED OR FOCAL CONTRAST UPTAKE BY CT;WITH/WITHOUT FOCAL/DISSEMINATED NODULESF igure 1.

4 Abnormal or suspected disease according to the LUGANO ClassificationThe LUGANO CLASSIFICATION is not drastically different from the previous guideline (IWG-NHL 2007) but there are important clarifications and modifications provided including the following key aspects: Abnormal or Suspected Disease for CT-based interpretationFDG-PET Interpretation in Lymphomas Standardized staging for FDG-avid lymphomas Response assessment in FDG-avid histologies is made according to the 5-Point Scale (5PS)2 Bone marrow biopsy no longer indicated for the routine staging of HL and most DLBC.

5 FDG-PET imaging should be used instead for the Interpretation in Lymphomas Progressive disease evaluation is determined by the Products of the Perpendicular Diameters (PPD) progression of single site. Progressive disease evaluation no longer includes Sum of the Products (SPD). Routine surveillance scans are discouraged to minimize unnecessary scans to patients. Splenic involvement is quantified with > 13 cm considered enlarged on CT by cranial to caudal length2 Barrington SF, Mikhaeel NG, Kostakoglu L, et al: Role of imaging in the staging and response assessment of lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group.

6 J Clin Oncol 32:3048-3058, JOURNEY. OUR | 3 Involved bone marrow at baseline (If required for subtype): Must be normal for CR (when all other sites are CR by CT) No evidence of Focal FDG-avid disease in marrow for CMR FDG-avid lymphoma subtypes Assess by 5PS Qualitative assessments should be based on SUV maps* Integrate with the CT based response TARGET EXTRANODAL LDI > CMTARGET NODAL LDI > CM Regrowth of resolved lesions New node > cm in any axis New extranodal site > cm in any axis New extranodal sites that must be unequivocal and attributable to lymphoma include.

7 Sites < cm in any axis, or Non-measurable truly assessable site of disease Up to 6 of the largest nodes, nodal masses or other lymphomatous lesions including extranodal disease measurable in two diameters (LDi and SDi) Represent overall disease burden /Include mediastinal and retroperitoneal disease, if involved All other disease not selected as target lesions consistent with lymphoma Abnormal nodes, extranodal sites, assessable sites*(*Cutaneous, gastrointestinal, bone lesions, pleural or pericardial effusions, ascites) Assess splenic size for involvement by vertical (cranial to caudal)

8 Length > 13 cm is considered involved For clinical trials, follow splenic nodules as target, non-target and new extranodal lesions Assess involvement qualitatively by CT Pre-existing persistent liver involvement with lymphoma prevents CR unless no longer avid New uptake in liver PD For clinical trials, follow hepatic nodules as target, non-target and new extranodal lesionsNon-target lesionsNew lesionsSplenic involementHepatic involvementFDG-PETBone marrowTar get lesions The LUGANO CLASSIFICATION Workflow* FDG-PET images need to be converted from images representing signal intensity to images of standardized uptake JOURNEY.

9 OUR | 4 PROGRESSION OF PRE-EXISTING splenomegaly NEW SPLENOMEGALYRECURRENT splenomegaly Splenic length must increase by > 50% in enlarged portion from no prior splenomegaly , splenic length must increase > 2 cm from baseline and be currently enlarged (> 13 cm).Spleen enlarged at baseline, normalizes, and subsequently becomes enlarged :Example:Example: At baseline the spleen was 15 cm (Enlarged portion is 2 cm). Thus a 1 cm increase to a spleen that is > 16 cm at follow-up is progression. At baseline the spleen was 10 cm. A 14 cm spleen at follow-up is consistent with progression.

10 A 12 cm spleen at follow-up is NOT consistent with progression. At baseline the spleen was 14 cm. At follow-up it normalizes to a size of 12 cm then subsequently grows to 14 cm. Progression is met when the spleen reaches 14 table represents the changes in the evaluation of the spleen compared to the IWG-NHL 2007 criteria:YOUR JOURNEY. OUR | 5 PET-CT which has been part of the lymphoma response guidelines since its incorporation in the IWG-NHL 2007, is already widely used as part of clinical trials and to evaluate patients outside of clinical trials. In a typical clinical trial with an FDG-avid lymphoma, CT scans occur more frequently than PET scans.